Malaria is emerging in Brazil as a major health threat especially in areas of new economic development. Recent reports both in the scientific and popular press have identified malaria as a significant impediment to economic development in Brazil. Compounding the existing problem is the emergence and spread of P. falciparum to the most commonly used antimalarials in Brazil. As a result of this reduced efficacy of the cheapest antimalarials, Brazilian treatment reverted to quinine/tetracycline in various regimens as the primary treatment in uncomplicated malaria. This represents one of the few sites in the world in which quinine is used widely for the treatment of uncomplicated malaria and reports of reduced efficacy or quinine failures have increased in recent years. A detailed characterization of this resistance and identification of its potential mechanism are critically needed. Quinine represents the final phase treatment in many situations and is still the recommended treatment for severe and complicated malaria throughout the world. Thus, emergence of resistance to quinine in P. falciparum could represent a severe setback in the fight against malaria and could have significant implications for treatment of malaria in Brazil, elsewhere in Latin America, and throughout the world. This is a new project and represents a collaboration between USAMRU- Brazil, FIOCRUZ and Harvard. The overall goal is to investigate drug resistance in P. falciparum malaria in Brazil. The project combines both field isolation of parasites from patients who have failed to respond to antimalarial drug treatment or whose parasites are recrudescent, indicative of reduced susceptibility to the drug and laboratory characterization of those parasites, including in vitro drug testing, biochemical and molecular characterization. The goal of the work presented here is to understand the profile of drug resistance in malaria parasites, primarily P. falciparum, in Brazil at the clinical, pharmacological and molecular levels. Of particular interest will be quinine resistant parasites. We will focus our efforts on recent isolates of P. falciparum from the Amazon region of Brazil. This project ties in directly with the goals of this ICIDR to decrease the morbidity and mortality of these important tropical diseases.